Mutations in ACTRT1 and its enhancer RNA elements lead to aberrant activation of Hedgehog signaling in inherited and sporadic basal cell carcinomas

• Published in: Nature Medicine Vol. 23; no. 10; pp. 1226 - 1233
• Main Authors: Bal, Elodie, Park, Hyun-Sook, Belaid-Choucair, Zakia, Kayserili, Hülya, Naville, Magali, Madrange, Marine, Chiticariu, Elena, Hadj-Rabia, Smail, Cagnard, Nicolas, Kuonen, Francois, Bachmann, Daniel, Huber, Marcel, Le Gall, Cindy, Côté, Francine, Hanein, Sylvain, Rosti, Rasim Özgür, Aslanger, Ayca Dilruba, Waisfisz, Quinten, Bodemer, Christine, Hermine, Olivier, Morice-Picard, Fanny, Labeille, Bruno, Caux, Frédéric, Mazereeuw-Hautier, Juliette, Philip, Nicole, Levy, Nicolas, Taieb, Alain, Avril, Marie-Françoise, Headon, Denis J, Gyapay, Gabor, Magnaldo, Thierry, Fraitag, Sylvie, Crollius, Hugues Roest, Vabres, Pierre, Hohl, Daniel, Munnich, Arnold, Smahi, Asma
• Format: Journal Article Magazine Article
• Language: English
• Published: New York Nature Publishing Group US 01-10-2017; Nature Publishing Group
• Subjects: 13/1; 13/109; 13/2; 13/44; 13/51; 13/95; 14; 14/1; 14/19; 14/28; 14/32; 14/34; 14/63; 38; 38/109; 38/44; 38/47; 38/61; 38/70; 38/71; 38/77; 38/90; 45; 631/208/200; 631/208/68; 631/67/581; 64/60; 82/1; 82/29; 82/51; 82/80; 82/83; 96; Aberration; Actin; Animals; Basal cell carcinoma; Biochemistry, Molecular Biology; Biomedicine; Cancer; Cancer Research; Carcinoma; Carcinoma, Basal Cell - genetics; Care and treatment; Cell activation; Cells; Cellular signal transduction; Chemical elements; Chromatin Immunoprecipitation; CRISPR-Cas Systems; Development and progression; Enhancer Elements, Genetic - genetics; Female; Gene Expression Profiling; Gene mutation; Genetic aspects; Genodermatosis; Genomics; Health aspects; Hedgehog protein; Hedgehog proteins; Hedgehog Proteins - metabolism; Heredity; High-Throughput Nucleotide Sequencing; Humans; Hypotrichosis - genetics; Infectious Diseases; Kinases; letter; Life Sciences; Male; Metabolic Diseases; Mice; Mice, Nude; Microfilament Proteins - genetics; Molecular Medicine; Mutation; Neoplasm Transplantation; Neurosciences; Next-generation sequencing; Polymerase Chain Reaction; Ribonucleic acid; RNA; Sequence Analysis, DNA; Signal Transduction; Signaling; Skin cancer; Skin Neoplasms - genetics
• ISSN: 1078-8956; 1546-170X; 1744-7933
• DOI: 10.1038/nm.4368

Inactivating mutations in
ACTRT1
or surrounding noncoding sequences transcribed into functional enhancer RNAs cause aberrant activation of Hedgehog signaling in both sporadic and inherited forms, such as Bazex–Dupré–Christol syndrome, of basal cell carcinoma. These findings identify a new tumor-suppressor gene and underscore the functional relevance of genomic alterations in noncoding transcribed regions in tumor development.
Basal cell carcinoma (BCC), the most common human cancer, results from aberrant activation of the Hedgehog signaling pathway
1
. Although most cases of BCC are sporadic, some forms are inherited, such as Bazex–Dupré–Christol syndrome (BDCS)—a cancer-prone genodermatosis with an X-linked, dominant inheritance pattern
2
. We have identified mutations in the
ACTRT1
gene, which encodes actin-related protein T1 (ARP-T1), in two of the six families with BDCS that were examined in this study. High-throughput sequencing in the four remaining families identified germline mutations in noncoding sequences surrounding
ACTRT1
. These mutations were located in transcribed sequences encoding enhancer RNAs (eRNAs)
3
,
4
,
5
and were shown to impair enhancer activity and
ACTRT1
expression. ARP-T1 was found to directly bind to the
GLI1
promoter, thus inhibiting
GLI1
expression, and loss of ARP-T1 led to activation of the Hedgehog pathway in individuals with BDCS. Moreover, exogenous expression of
ACTRT1
reduced the
in vitro
and
in vivo
proliferation rates of cell lines with aberrant activation of the Hedgehog signaling pathway. In summary, our study identifies a disease mechanism in BCC involving mutations in regulatory noncoding elements and uncovers the tumor-suppressor properties of
ACTRT1
.